Insulin resistance occurs commonly in diseases of the metabolic syndrome, particularly obesity and Type 2 diabetes. However, the mechanisms of insulin resistance are poorly understood. Recent studies have implicated lipid-induced activation of inflammatory pathways, specifically IKK/IKkappaB/NF-kappaB, in the pathogenesis of insulin resistance. The goals of the current proposal are to provide the candidate with the necessary theoretical and practical training to address the role of the IKK/IkappaB/NF-kappaB pathway in the development of insulin resistance, and to allow him to begin to master this area. Specifically, there are three overall Training aims: Aim 1. To expand the candidate's theoretical knowledge of insulin resistance, lipid metabolism and inflammation. Aim 2. To gain practical experience and theoretical knowledge of experimental design, and data interpretation. Aim 3. To learn the techniques required for the execution and analysis of experiments in animal model(s) of obesity and diabetes. This training will be acquired during the development of a research project that has the following specific Research Aims: Aim 1. To determine the role of the IKK/IkappaB/NF-kappaB pathway in the development of skeletal muscle insulin resistance resulting from acute lipid infusion (acute model of lipid-induced insulin resistance). Aim 2. To determine the role of the IKK/IkappaB/NF-kappaB pathway in the development of skeletal muscle insulin resistance in diet-induced obesity (chronic model of lipid-induced insulin resistance). Aim 3. To determine the effects of Pioglitazone, an insulin sensitizer and regulator of lipid metabolism, on the activity of the IKK/IkappaB/NF-kappaB pathway in insulin resistant states.